Investigation of the Role of PUFA Metabolism in Breast Cancer Using a Rank-Based Random Forest Algorithm

SIMPLE SUMMARY: Polyunsaturated fatty acids (PUFAs) and their derivatives, oxylipins, are a constant focus of cancer research due to the relationship between cancer and processes of energy metabolism and inflammation, where a PUFA system is an active player. Only recently have methods been developed that allow for studying such complex systems. Using the Rank-based Random Forest (RF) model, we show that PUFA metabolism genes are critical for the pathogenesis of breast cancer (BC); BC subtypes differ in PUFA metabolism gene expression. The enrichment of BC subtypes with various genes associated with oxylipin signaling pathways indicates a different contribution of these compounds to the biology of subtypes. ABSTRACT: Polyunsaturated fatty acid (PUFA) metabolism is currently a focus in cancer research due to PUFAs functioning as structural components of the membrane matrix, as fuel sources for energy production, and as sources of secondary messengers, so called oxylipins, important players of inflammatory processes. Although breast cancer (BC) is the leading cause of cancer death among women worldwide, no systematic study of PUFA metabolism as a system of interrelated processes in this disease has been carried out. Here, we implemented a Boruta-based feature selection algorithm to determine the list of most important PUFA metabolism genes altered in breast cancer tissues compared with in normal tissues. A rank-based Random Forest (RF) model was built on the selected gene list (33 genes) and applied to predict the cancer phenotype to ascertain the PUFA genes involved in cancerogenesis. It showed high-performance of dichotomic classification (balanced accuracy of 0.94, ROC AUC 0.99) We also retrieved a list of the important PUFA genes (46 genes) that differed between molecular subtypes at the level of breast cancer molecular subtypes. The balanced accuracy of the classification model built on the specified genes was 0.82, while the ROC AUC for the sensitivity analysis was 0.85. Specific patterns of PUFA metabolic changes were obtained for each molecular subtype of breast cancer. These results show evidence that (1) PUFA metabolism genes are critical for the pathogenesis of breast cancer; (2) BC subtypes differ in PUFA metabolism genes expression; and (3) the lists of genes selected in the models are enriched with genes involved in the metabolism of signaling lipids.